| The incidence rate of Graves' disease is the highest of any of the endocrine autoimmune diseases. This disease is caused by the production of autoantibodies that bind the thyroid stimulating hormone receptor (TSHR) and stimulate the thyroid to secrete thyroid hormones leading to hyperthyroidism. Importantly, although the thyroid organ itself is not normally destroyed in the disease, there is at the moment, no long-term effective treatment for Graves' disease. Therefore, by understanding the development of the disease, one might be able immunomodulate it.; Spontaneous models of autoimmune Graves' disease are not available, however our laboratory has developed an experimental model of Graves' disease, where female Balb/c mice are repeatedly immunized with TSHR over a long period of time (months) until a subset of anti-TSHR autoantibodies evolve into thyroid-stimulatory antibodies that are pathogenic. Since the target for autoantibodies is a protein, it is highly likely that the induction of the disease requires T cells and B cells.; The T cell response in our model of Graves' disease was determined by assaying proliferative responses and TcR beta chain expression of subgroups of T cells from splenic and lymph node cells after TSHR immunizations. We show a transient and moderate response against TSHR early in the immunization schedule of mice. Although oligoclonal, the response was moderate and largely against a single peptide. This would argue that T cell epitope spreading was not occurring, at least with respect to dominant epitopes, and opens the possibility that T cells may not play a crucial role when autoantibodies evolve into stimulatory and pathogenic antibodies.; To begin to understand the evolution of the B cells, we sequenced the CDR3s from the Ig heavy chains from examples of mice at different stages of disease induction. We present data that demonstrate an association between a higher number of somatic replacement mutations in the sequences from a TSHR-immunized mouse and high T4 values. Although these results need to be generalized, we hypothesize that the higher numbers of somatic mutations in the antibodies may partly explain how anti-TSHR autoantibodies evolve into stimulatory autoantibodies. |
